Dissolution testing is often performed as part of preparing and evaluating soluble materials, particularly pharmaceutical dosage forms (e.g., tablets, capsules, and the like) consisting of a therapeutically effective amount of active drug carried by an excipient material. Typically, dosage forms are dropped into test vessels that contain dissolution media of a predetermined volume and chemical composition. For instance, the composition may have a pH factor that emulates a gastro-intestinal environment. Dissolution testing can be useful, for example, in studying the drug release characteristics of the dosage form or in evaluating the quality control of the process used in forming the dose. To ensure validation of the data generated from dissolution-related procedures, dissolution testing is often carried out according to guidelines approved or specified by certain entities such as United States Pharmacopoeia (USP), in which case the testing must be conducted within various parametric ranges. The parameters may include dissolution media temperature, the amount of allowable evaporation-related loss, and the use, position and speed of agitation devices, dosage-retention devices, and other instruments operating in the test vessel.
As a dosage form is dissolving in the test vessel of a dissolution system, optics-based measurements of samples of the solution may be taken at predetermined time intervals through the operation of analytical equipment such as a spectrophotometer. The analytical equipment may determine analyte (e.g. active drug) concentration and/or other properties. The dissolution profile for the dosage form under evaluation—i.e., the percentage of analytes dissolved in the test media at a certain point in time or over a certain period of time—can be calculated from the measurement of analyte concentration in the sample taken. In one specific method employing a spectrophotometer, sometimes referred to as the sipper method, dissolution media samples are pumped from the test vessel(s) to a sample cell contained within the spectrophotometer, scanned while residing in the sample cell, and in some procedures then returned to the test vessel(s). In another more recently developed method, sometimes referred to as the in situ method, a fiber-optic “dip probe” is inserted directly in a test vessel. The dip probe includes one or more optical fibers that communicate with the spectrophotometer. In the in situ technique, the spectrophotometer thus does not require a sample cell as the dip probe serves a similar function. Measurements are taken directly in the test vessel and thus optical signals rather than liquid samples are transported between the test vessel and the spectrophotometer via optical fibers.
In conjunction with dissolution testing, it is useful to measure the volume of media residing in a given vessel. For example, it may be desirable to control the precise amount of media added to a vessel such as during a media filling, refilling, replenishing, replacement or return procedure, a solvent or reagent addition procedure, etc. Likewise, it may be desirable to control the precise amount of media removed from a vessel such as when transferring a sample aliquot to an analyzing device. Conventionally, volumetric measurements of media are taken outside of the vessel (i.e., ex situ). Ex situ measurements of volume are imprecise because one must account for the volume of liquid left in the media supply line or media aspiration line. An alternative conventional technique is to first tare the empty vessel, add an unknown quantity of media to the vessel, and weigh the vessel and its media contents and then subtract the tare weight of the vessel to obtain the weight of the media contained in the vessel. The volume of the media is then calculated from this weight value and the known specific gravity of the media. This latter technique requires weighing procedures that are performed outside of the dissolution test apparatus and cannot be integrated with the dissolution test procedure. Thus, vessels of the dissolution test apparatus must be taken off-line and removed from the dissolution test apparatus. Moreover, such weight measurements cannot be taken in real-time or on-demand during dissolution testing.
Accordingly, there is a need for methods and apparatus for obtaining volumetric measurements of media directly at the vessels of a dissolution test apparatus.